Coating Formulations for Scoring or Cutting Balloon Catheters

ABSTRACT

The present invention is related to scoring or cutting balloon catheters carrying at least on a portion of their surface at least one oxidation-insensitive drug or oxidation-insensitive polymer-free drug preparation and at least one lipophilic antioxidant at a ratio of 3-100% by weight of the at least one lipophilic antioxidant in relation to 100% by weight of the drug, wherein the at least one oxidation-insensitive drug is selected of taxanes, thalidomide, statins, corticoids and lipophilic derivatives of corticoids, and the at least one lipophilic antioxidant is selected of nordihydroguaiaretic acid, resveratrol and propyl gallate.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/628,608 filedSep. 27, 2012, which is a continuation of PCT/EP2010/066754, filed Nov.3, 2010, which claims the benefit of EP Application No. 10160347.0,filed Apr. 19, 2010, the full disclosures of which are incorporatedherein by reference in their entirety. The present application isrelated to Applicant's co-pending application Ser. No. 13/628,627 filedSep. 27, 2012 which claims the benefit of EP application No. 10160347.0,filed Apr. 19, 2010 and Applicant's co-pending application Ser. No.13/641,941, filed Nov. 3, 2010 which claims priority to EP applicationNo. 10160349.6, filed Apr. 19, 2010.

BACKGROUND

1. Field of the Invention

The invention relates to the transfer of a drug loosely adhering to thesurface of a scoring or cutting balloon catheter to a site inside thebody, usually in a diseased blood vessel. The preferred application islocal drug therapy during percutaneous transluminal angioplasty (PTA) orpercutaneous transluminal coronary angioplasty (PTCA). The interventionsare performed to restore blood flow in stenotic or occluded bloodvessels, usually into arteries. A catheter is introduced in a majorartery. At the distal end the catheter carries a cylindrical balloon infolded state with very small diameter and additional tools or structureswhich scratch or cut the luminal surface of the treated blood vessel ortissue. In the folded state the balloon can enter or pass the stenoticor occluded segment of e.g. a blood vessel. Once positioned in thenarrowed segment, the balloon is inflated to enlarge the lumen of theblood vessel to its original diameter. Simultaneously, a drug may betransferred to the vessel wall to prevent early and late re-narrowingdue to hyperproliferation of the injured vessel wall.

Medical devices may contain drugs either to improve the tolerance,efficacy or in vivo lifetime of the device or the device serves ascarrier for the drug. In any case the dose density (e.g. mg drug/mgdevice or mg drug/mm2 device surface) , chemical stability, adherence,release rate, and total amount released are important and frequentlycritical features of the drug formulation. These properties are the morecritical the more the requirements during production and application ofthe device vary or may even be contradictory. Drug-coated angioplastycatheters are typical examples: the drug coating must adhere firmly totolerate mechanical stress during production including folding ofballoons, crimping of stents, packaging, transportation to customers,and during final application, which involves the passage through anarrow hemostatic valve, an introductory sheath or guiding catheter anda variable distance through possibly tortuous and narrow blood vessels.When the balloon is inflated the drug should be released within a minuteor less as rapidly and as completely as possible. The problem wasdemonstrated by Cremers et al. (Cremers B, Biedermann M, Mahnkopf D,Bdhm M, Scheller B. Comparison of two different paclitaxel-coatedballoon catheters in the porcine coronary restenosis model. Clin ResCardiol 2009; 98:325-330) who retrieved as much as 50% of the dose fromballoons after expansion for one minute in coronary arteries of pigs,whereas other catheters coated with the same drug and dose but in adifferent formulation released more than 95%. Almost perfect results(i.e., loss of only 10% of dose and residual drug on the balloon afterexpansion in an artery of about 10%) were achieved with a rigidprototype balloon (Scheller B, Speck U, Abramjuk C, Bernhardt U, Bohm M,Nickenig G. Paclitaxel balloon coating—a novel method for prevention andtherapy of restenosis. Circulation 2004; 110: 810-814). The applicationof the same coating composition to more flexible modern ballooncatheters resulted in problems, i.e., larger premature loss of the drug.The coating of scoring or cutting balloons with drugs in a reliable waywith a dose which is sufficient to be efficacious imposes additionalproblems because of the more complex structure of the device and themore complex production process.

2. Prior Art

Protection from premature drug release. Premature release of a drug froma balloon is a major problem which has been addressed by a variety ofmethods. Some of them are mechanical, e.g. the use of protection tubes,sleeves, envelops. Examples are U.S. Pat. No. 5,370,614, U.S. Pat. No.6,306,166, and U.S. Pat. No. 6,616,650 disclosing various protectivesheaths which are retracted before the balloon is inflated, or U.S. Pat.No. 6,419,692 proposing a cover which bursts during balloon expansion. Adifferent approach is taken in U.S. Pat. No. 5,893,840 disclosingstructured balloon membranes with tiny cavities, V$ 0 94/23787 withroughened balloon membranes to enhance the adherence of coating, or morerecently U.S. Pat. No. 7,108,684 proposing a pouch which protects thedrug-containing layer on the balloon and N.\0 2009/066330 disclosingmethods placing the drug selectively under the folds of a foldedballoon. Although efficacious these methods have the disadvantage ofincreasing the complexity and cost of production or make handling of thedevices more difficult or add to the diameter of the devices (which mustbe kept as small as possible to facilitate passage through stenoticlesions) . In some embodiments the protective membranes or perforatedmembranes interfere with the scoring components of the balloons orprevent a homogeneous transfer of the drug to the tissue or even put thepatient at risk. None of these methods has been applied to scoring orcutting balloons and nothing is known about problems which will arisefrom the increasing complexity and mechanical problems or from adisturbance of the protecting envelops by the scoring or cuttingstructures and vice-versa.

Other approaches use either physical or chemical methods to control therelease of drugs from a balloon surface, e.g. U.S. Pat. No. 5,304,121describes a hydrogel which releases the drug only after exposure to atriggering agent; U.S. Pat. No. 5,199,951 relies on thermal activation;according to U.S. Pat. No. 7,445,792 a lipophilic ̂hydration inhibitor'protects water-soluble drugs from premature release; and according toU.S. Pat. No. 5,370,614 a viscous matrix protects the drug frompremature release, however, the viscous matrix must be protected by asheath during the passage to the stenotic vessel segment. None of themethods has been tested in practice and proven to fulfill therequirements for fast, reliable and complete drug transfer to the targettissue. None of the methods has been designed to be used with Otherapproaches use either physical or chemical methods to control therelease of drugs scoring or cutting balloons.

Numerous methods of sustained drug release are known and successfullyused in practice but are not applicable to medical devices which are incontact with the target tissue for only a few seconds or minutes.Sustained drug release is usually achieved by embedding the drug in apolymer which restricts the diffusion rate to the surface and in thisway controls the transfer into the adjacent tissue.

Therefore, a need remains for a method or formulation which protects thecoating from premature losses during production, handling, and on theway to the lesion and still allows the immediate and complete release ofthe active ingredient at a location and point in time determined by theuser. During the production process this problem is even more severe forscoring and cutting balloons because of the more complex structure ofthe product. Scoring and cutting balloons have merits in the treatmentof certain lesions, e.g. if the conventional smooth balloons tend todislocate during inflation or if a controlled and predetermined injuryof the vessel wall is preferred to an uncontrolled dissection duringballoon inflation. Nevertheless, the problem of renarrowing of thevessel lumen due to excessive neointimal proliferation as a reaction tothe unavoidable injury during dilatation is the same as withconventional balloon catheters.

An advantageous way to control adherence and release of a drug from amedical device, e.g., an angioplasty balloon, is the selection of asuitable formulation and coating which do not require mechanicalprotection, or additional physical or chemical interaction with thecoating except the usual operation of the device e.g. inflation of afolded balloon to induce the release of the drug. Although desirable andfrequently tried, the conflicting objectives of perfect adherence duringproduction and before use and immediate release at the site of actionmake it a difficult task. A large variety of patent applications vaguelydisclose measures, compositions and devices to solve this problem forconventional balloon catheters either by the selection of drugs, thechoice of specific coating processes or formulations containing variousadditives. Long lists of compounds have been copied from textbooks ofchemistry, pharmacology, or pharmacy but even with extensiveexperimentation disclosures are not sufficiently clear to allow a personfamiliar with the subject and skilled in the art to come to asatisfactory solution without an inventive step. Examples of prior artare US 2008/0118544 reciting an excessive number of substances andsubstance classes or U.S. Pat. No. 7,445,795 which discloses the use ofhydration inhibitors' not applicable to the preferred class of verylipophilic drugs which require hydration enhancers' or ‘dispersion anddissolution enhancers’ as e.g. disclosed in WO 2004/028582. Although thehydrophilic additives (which may be regarded as ‘hydration enhancer’)work quite well on certain conventional balloon membranes (Scheller B,Speck U, Abramjuk C, Bernhardt U, Bohm M, Nickenig G. Paclitaxel ballooncoating—a novel method for prevention and therapy of restenosis.Circulation 2004; 110: 810-814) the adherence to various modernconventional or scoring PTA or PTCA balloons is either too weak or tootight resulting in premature loss of a major proportion of the drug orincomplete release at the target site. None of the known compositionshas been tried on scoring or cutting balloon catheters.

Antioxidants. In theory, antioxidants address an almost universalfeature of diseased tissue, namely the ‘reactive oxygen species’, andshould have widespread medical applications. In practice, only very fewcontrolled clinical trials have shown beneficial effects of antioxidants(Suzuki K. Antioxidants for therapeutic use: Why are only a few drugs inclinical use'? Advanced Drug Delivery Reviews 2009;61:287-289).Antioxidants are mentioned as potentially useful drugs for the treatmentof focal vascular disease such as stenosis, restenosis, atheroscleroticplaques, and vulnerable plaques in US 2009/0136560 with no additive, inU.S. Pat. No. 5,571,523 as agents inducing apoptosis in vascular smoothmuscle cells, in \\a 2004/022124 either as active drugs or as ̂hydrationinhibitors'. In US 2008/0241215 probucol, a drug approved for thetreatment of hyperlipidemia, a known risk factor for atheriosclerosis,is proposed as the active ingredient in stent coating, either alone orcombined with rapamycin or another anti-restenotic agent in aslow-release formulation. U.S. Pat. No. 6,211,247 claims pharmaceuticalcompositions containing an effective dose of resveratrol for preventingor treating various vascular pathologies following coronaryinterventions. Similarly, US 2007/0037739 discloses local deliverysystems comprising various bioactive agents including resveratrol whicheither alone or in the specified combinations are suitable for treatingor preventing abnormal luminal cell proliferation. None of theabove-mentioned documents contains data encouraging the use as additivesto a lipophilic drug to delay the release rate of the drug and nospecific compositions are disclosed which address the above-mentionedproblems of adhesion of a drug before the target lesion is reached andimmediate release when required.

Small proportions of antioxidants are commonly used to protect drugs ornutrients from decomposition by oxygen or oxidation, an applicationwhich has also been proposed for drugs coated on implantable medicaldevices such as stents (US 2007/0020380, US 2009/0246253) or ballooncatheters (US 2005/0037048, US 2009/0246252, especially paragraph [105]). However, antioxidants are commonly used in proportions of lessthan 1% by weight in relation to 100% by weight of the drug. Normally itis intended to use as less antioxidant as possible, i.e., less than 0.1%by weight in relation to 100% by weight of the drug (Voigt R. Lehrbuchder pharmazeutischen Technologie. 5. Edition, Verlag Chemie,Wein-heim-Deerfield Beach, Fla.-Basel, 1984) . US2005/0037048 disclosesa specific example which refers to a selected drug in a polymeric matrixrequiring an unusually high proportion of antioxidant.

Again, none of the above mentioned documents provides any hint to anadvantage in using antioxidants in combination with stable (i.e.oxidation-resistant drugs) and/ or at dose levels which provide notherapeutic or prophylactic action.

Present Invention. The problem underlying the present invention was theprovision of a scoring or cutting balloon catheter with an improvedadherence of the drug without negative effect on the release of the drugat the target site.

The problem was solved by a scoring or cutting balloon catheteraccording to claim 1. In other words, the problem was solved by ascoring or cutting balloon catheter carrying at least on a portion ofits surface at least one oxidation-insensitive drug oroxidation-insensitive polymer-free drug preparation and at least onelipophilic antioxidant at a ratio of 3-100% by weight of the at leastone lipophilic antioxidant in relation to 100% by weight of the drug,wherein the at least one oxidation-insensitive drug is selected oftaxanes, thalidomide, statins, corticoids and lipophilic derivatives ofcorticoids, and the at least one lipophilic antioxidant is selected ofnordihydroguaiaretic acid, resveratrol and propyl gallate.“Polymer-free” means that no additional polymer is part of the coating.Preferred embodiments are disclosed in the dependant claims. Usually,antioxidants are used to stabilize oxidation-sensitive drugs againstdegradation by oxygen. They are considered useless in this regard if thedrug is stable against oxidative degradation, i.e. if the drug isoxidation-insensitive. Below, the terms “oxidation-insensitive drug”,“active drug” and “drug” are used interchangeable all meaning anoxidation-insensitive drug if the invention is concerned.

During testing of a large variety of coating methods, additives and drugcombinations the surprising discovery was made that certain lipophilicantioxidants added to less or even more lipophilic and more or lesswater soluble drugs, which are oxidation-insensitive, in a defined massratio significantly increase the adherence of the drug to scoring andcutting balloons during handling and on the way to the target lesioneven if the target lesion is located far away from the site where thedevice first enters a blood-filled introductory sheath, guiding catheteror vessel containing During testing of a large variety of coatingmethods, additives and drug combinations the rapidly flowing blood. Thiswas also tested with scoring balloons. In spite of the additionalmechanical stress (as compared to conventional balloons) imposed on thecoating due the movement of the scoring wires surrounding the foldedballoons the loss of the drug during the passage through a narrowhemostatic valve and a curved guiding catheter was very low. Thus, atleast one lipophilic antioxidant in an amount of 3-100% by weight isused as an adherence improver for drugs coated on a scoring or cuttingballoon catheter during this initial step of introducing the medicaldevice into the vasculature. The wording “at least one lipophilicantioxidant” means that single antioxidants but also mixtures ofdifferent antioxidants are included. Other substances or pharmaceuticalcompounds may be added to further adjust the properties of the productto the demand in respect of stability or other pharmaceuticalrequirements and tolerance etc.

Examples of active drugs are inhibitors of cell proliferation,preferably taxanes such as paclitaxel, docetaxel and protaxel.Alternatively, specific inhibitors of neovascularization such asthalidomide, statins like atorvastatin, cerivastatin, fluvastatin oranti-inflammatory drugs like corticoids or even more preferredlipophilic derivatives of corticoids such as betamethasone diproprionateor dexa-methasone-21-palmitate are examples of oxidation-insensitivedrugs. Various drugs may be applied or combined if differentpharmacological actions are required or efficacy or tolerance is to beimproved. Thus, the wording “at least one drug or drug preparation”means that single drugs but also mixtures of different drugs areincluded. Preferred drugs are either lipophilic (partition coefficientbetween n-butanol and water >10, or display very poor water solubility(<1 mg/ml, 20° C.). Preferred are those drugs which in dry state arechemically stable during long-term storage without the addition of anantioxidant, e.g., paclitaxel and other taxanes, statins, thalidomide,corticosteroids and lipophilic derivatives of corticoids. Thereof, thepreferred ones are paclitaxel, protaxel and docetaxel with paclitaxelbeing the most preferred drug. Drugs must be used in a dose rangeproviding the desired effect without compromising the technical featuresof the coated balloon (balloon catheter) such as flexibility. Apreferred dose range is between 1 and 10 pg/mm 2 balloon surface, mostpreferred up to 6 g/mm².

The lipophilic antioxidants are antioxidants which are solid attemperatures up to 40° C. Preferred are nordihydroguaiaretic acid,propyl gallate and resveratrol, more preferred nordihydroguaiaretic acidand resveratrol, most preferred only resveratrol. Probucol is not apreferred additive.

Combinations of these antioxidants with the above-mentioned drugs showedan improved adherence. Different combinations, especially with otheroxidation-insensitive drugs, did not how a significantly improvedadherence or required very high amounts of the antioxidant which impairsthe mechanical features of the balloons (much more than 100% by weightin relation to 100% by weight of the drug).

Lipophilic antioxidant means that the partition coefficient of theantioxidant between nbutanol and water is >1, more preferred >10 andeven more preferred >100.

Preferably, the drug is more lipophilic than the antioxidant, i.e., thepartition coefficient between n-butanol and water of the drug is higherthan the partition coefficient between n-utanol and water of theantioxidant. If, however, an excipient prevents premature loss of thedrug from the medical device and/or enhances the fast and completetransfer to the tissue it shall not be excluded because of itsphysicochemical properties.

At the dose density used the chosen antioxidants do not display relevanttherapeutic or prophylactic effects in respect of the disease which istreated by the coated medical device nor is the relative amount of theantioxidant chosen to protect the drug from oxidative decomposition.This means that a non-bioactive dose of the antioxidant is preferred.The dose density and the mass relation of the antioxidant to the drugare solely optimized in respect of adherence of the drug to and releasefrom the medical device surface. The antioxidant dose on the medicaldevice is too low to provide the desired pharmacological effect, i.e.,it is ineffective on its own. The antioxidant on the medical device isnot required to protect the active drug (e.g., the antiproliferativedrug) from oxidative decomposition during production, sterilization andstorage; at least it is not required at the dose or concentrationapplied according to this invention. Not required' means that the activedrug is stable enough without the antioxidant or at an antioxidant doseor dose density or ratio to the active drug below the dose according tothe present invention. Sufficient stability' means that less than 5% ofthe active drug is lost due to oxidative decomposition between thecoating of the device and the use in patients one year after productionif stored at ambient temperature (=drug or drug preparation stableagainst oxidative decomposition, air-oxygen exposure not excluded) . Inconclusion the invention relates to a combination of an antioxidant witha drug which needs no protection from oxidative decomposition or atleast a dose of the antioxidant which surpasses the amount ofantioxidant required protecting the drug from oxidation by itsantioxidant action. The antioxidant serves as additive or excipient notfunctioning as a stabilizer for an oxidation-sensitive biologicallyactive ingredient (drug) nor displaying a therapeutic or prophylacticeffect on its own at the selected dose.

The dose of the antioxidant on the surface of a medical device may bedefined in respect of the therapeutic drug. Preferred relationships(weight/weight) are 3-100% antioxidant of the weight of the drug. Forexample, if the dose density of the drug is 5 g/mm2 device surface, theamount of antioxidant is 0.15-5.0 g/mm2 . Higher proportions of theantioxidant may be selected if either the drug is applied at a dosebelow 3 pg/mm2 device surface or the adherence of the drug to the devicesurface is further improved. The antioxidant load of the device mayreach 10 g/mm2. A higher load is possible. Other preferred ranges forthe relationship of antioxidant to drug on a weight/weight basis are5-100%, more preferred 10-100%, and even more preferred 20-100% and mostpreferred 50-100% in relation to 100% of the drug. Especially the rangeof 50-100% on a weight/weight basis enhances the adherence significantly(see Example 3). The relationship may also be defined in respect ofmoles: in a preferred embodiment the antioxidant is present from 10 mole% relative to the drug to 200 mole %.

Higher amounts of the antioxidant may be useful; they may be onlyexcluded if they display on their own significant pharmacologicalprophylactic or therapeutic effects in respect of the disease to betreated.

If more than one drug is used the total weight of the drugs or the totalmoles of the drugs serve as basis for the calculation of the amount ofthe antioxidant. If more than one antioxidant is used the total weightof the antioxidants or the total moles of the antioxidants serve asbasis for the calculation of the amount of the antioxidants.

Other well tolerated and approved additives and/or excipients may beapplied to further improve the mechanical or pharmaceutical propertiesof the coating. Polymer-free coating compositions are preferred. It is aspecial advantage of the present compositions that they do not requirethe use of polymers to prevent premature release of the drug.Nevertheless, small amounts of pharmaceutically acceptable polymers suchas polyacrylic acids may be added, e.g., to improve the distribution ofthe drug on the balloon or adherence of the dry coating during handling.Small amounts mean about 1-20% by weight in relation to 100% by weightof the drug(s) . If polymers are used substances with low to moderatemolecular weight, i.e., 2000 to 50 000 D are preferred.

Usually, drugs and mixtures of drugs with additives are coated onmedical devices as liquid formulations in volatile solvents, accordingto the current invention preferably without addition of a polymer, i.e.polymer-free. The choice of solvent is important for the distribution ofthe drug on the device, especially if the device is coated at anadvanced stage of production, An advanced stage of production of ascoring or cutting balloon may include the scoring or cutting elementsof the device, the structures required to fix these elements and analready folded balloon. The solvents further determine the structure ofthe coating in dry state and the adherence and release of the drug fromthe surface. Preferred organic solvents are acetone, tetrahydrofuran,and various alcohols such as methanol and ethanol. Usually, 1 to 30%(volume /volume) water is added. The drug or drugs and the antioxidentsmay be applied at the same time dissolved in the same solvent or mixtureof solvents. Alternatively, they may be separately dissolved in the sameor different solvents and sequentially applied. The solution(s) is/arepolymer-free in either case. In a preferred embodiment, the scoring orcutting balloon catheter has been polymer-free coated with at least oneoxidation-insensitive drug and at least one antioxidant both togetherdissolved in tetrahydrofuran or a mixture of solvents containing morethan 25% (v/v) tetrahydrofuran or each separately dissolved optionallyselecting a different solvent for the at least one lipophilicantioxidant. Another preferred embodiment is based on a scoring orcutting balloon catheter, which has been polymer-free coated with atleast one oxidation-insensitive drug and at least one antioxidant bothtogether dissolved in acetone or a mixture of solvents containing morethan 25% (v/v) acetone or each separately dissolved optionally selectinga different solvent for the at least one lipophilic antioxidant. Coatingwith dry particles such as micro- or nano-particles, crystals, capsulesetc. or particles suspended in a liquid preparation is possible. Coatingwith particles may be facilitated by a roughened or sticky surface ofthe medical device.

A variety of coating procedures providing more or less uniform layers onmedical devices are known from the literature and are disclosed inpatent applications. These include simple dipping, spraying, and methodsproviding precise doses and homogeneous distributions (e.g., WO2009/018816) . Coating may be applied stepwise, either as multiplelayers of the same composition or as layers with different compositionse.g. the drug first and the antioxidant second or in the opposite order.All these methods may be applied to the formulations of the currentinvention. The sequential coating with, e.g., (a) the drug first and (b)second the antioxidant dissolved in a solvent in which the drug ispoorly soluble by, e.g., spraying results in substantially separatelayers. This is completely different from the application ofantioxidants for chemical protection of oxidation sensitive drugs whichrequires a homogeneous mixing of the antioxidant with the drug.

Thus, a preferred embodiment of the present invention is a scoring orcutting balloon catheter, which has been polymer-free sequentiallycoated with at least one oxidation-insensitive drug and at least onelipophilic antioxidant in a way that the oxidation-insensitive drug andthe antioxidant are not homogeneously mixed.

Furthermore, coated scoring or cutting balloon catheter may be driedunder different conditions such as temperature, air flow, gascomposition, and pressure at different stages of the production process.They may be stored in water-vapor-tight seals with a separately packedwater absorbing-agent within the seal.

Subject of the current invention are scoring or cutting ballooncatheters, e.g., catheters for angioplasty or coronary angioplasty.Preferred are scoring or cutting balloon catheters for shortlasting useduring an interventional image guided therapy. Short lasting use meansthat the device is not implanted but eliminated from the body when theprocedure is finished, usually within less than 10 minutes, but neverlater than a few, preferably 5, hours after the end of the procedure.Atheters may contain balloon membranes made from various polymers andcopolymers , polyamides (nylon 12, pebax), polyethylenes, polyurethanes,various polyvinyls and the like. Independently of the type of material,the adherence and release properties of drugs are improved by theaddition of lipophilic antioxidants. Furthermore, catheters compriseelements which are aimed at scoring or cutting the surfaces in directcontact with the inflated balloons, e.g. wires with various profiles, orprotrusions of the balloon surface.

The scoring or cutting balloon catheter carries the at least one drug ordrug preparation and the at least one lipophilic antioxidant at least ona portion of its surface which is aimed at coming into close contactwith the tissue to be treated, e.g., the balloon at the distal portionof a catheter shaft. This means that at least 5%, preferably more than50%, most preferably more than 90% of the surface is coated. The balloonof a scoring or cutting balloon catheter has a central cylindrical partand two opposite conical ends. If less than 100% of the ballooncatheter's surface is coated, it is preferred that the cylindrical partis coated and that at least parts of or the complete conical ends remainuncoated.

Another embodiment is a scoring or cutting balloon catheter carrying atleast on a portion of its surface polymer-free at least one Limus drugor Limus drug preparation and at least one lipophilic antioxidant, whichis nordihydroguaia-retic acid or resveratrol, preferably resveratrol, ata ratio of 3-100% by weight of the at least one lipophilic antioxidantin relation to 100% by weight of the drug.

Preferably, the Limus drug is an mTOR inhibitor, more preferablyselected from sirolimus, everolimus, zotarolimus, biolimus andtemsirolimus, most preferred sirolimus. Concerning preferred ways ofcarrying out this embodiment, the same applies as described above withrespect to the combination of oxidation-insensitive drugs/drugpreparations and lipophilic antioxidants.

Below, the invention is described by means of Examples.

EXAMPLE 1

Balloons for percutaneous transluminal coronary angioplasty type A(AngioSculpt 3.5-20 mm, AngioScore, Inc., Fremont Calif., USA) werecoated either with aclitaxel alone or combined with iopromide (iodinatedcontrast agent according to WO 02/076509) or different amounts ofbutylated hydroxy-toluene (BHT); solvent: acetone/ethanol/H2O. Coatedballoons were tested in respect of paclitaxel loss during the passagethrough a hemostatic valve, Medtronic Launcher JL 3.5 6F guidingcatheter and one minute in stirred blood (37° C.). When admixed atsufficient concentration to the coating solution, BHT improved theadhesion of paclitaxel.

Catheter Loss on the way to the Coating solution Labeling lesion % ofdose No additive 1 24 2 40 Iopromide as an additive; ca. 3 49 0.5 mg/mgpaclitaxel 4 34 BHT 5% = 0.05 mg BHT/mg 5 15 paclitaxel 6 26 BHT 24% =0.24 mg BHT/mg 7 10 paclitaxel 8 6

EXAMPLE 2

Balloons for percutaneous transluminal coronary angioplasty type A werecoated either with paclitaxel alone or combined with iopromide(iodinated contrast agent according to WO 02/076509), see example 2, orbutylated hydroxytoluene (BHT) or nordihydroguaiaretic acid.

Coated balloons were tested in respect of paclitaxel loss during thepassage through a hemostatic valve, a Medtronic Launcher JL 3.5 6Fguiding catheter and in stirred blood (37° C.) for one minute. Whenadmixed at sufficient concentration to the coating solution, lipophilicantioxidants improve the adhesion of paclitaxel whereas the releaseduring balloon inflation in a coronary artery (determined in separateexperiments) was not impaired.

Loss on the Residual way to the paclitaxel lesion % on balloons Coatingsolution Labeling of dose % of dose No additive acetone/ Control 32 Nodata ethanol/H₂O 1, 2 Iopromide as an Control 42 ~10   additive; ca. 0.5mg/ 3, 4 mg paclitaxel; acetone/ ethanol/H₂O BHT 24% = 0.24 mg A 15.3 ±9.5  11 BHT/mg paclitaxes; acetone/ethanol/H₂O BHT 24% = 0.24 mg B 3.4 ±4.8 13 BHT/mg paclitaxes; tetrahydrofuran/ ethanol/H₂ONordihydroguaiaretic C 4.2 ± 7.2 No data acid 35% = 0.35 mg/mgpaclitaxel; acetone/ ethanol/H₂O

EXAMPLE 3

Balloons for percutaneous transluminal coronary angioplasty type A werecoated either with paclitaxel without resveratrol or combined withresveratrol. Coated balloons were tested in respect of paclitaxel lossas described in example 1. When admixed at sufficient concentration tothe coating solution, resveratrol improved the adhesion of paclitaxel.

Loss on the way to Coating solution Labeling the lesion % of doseResveratrol 0% acetaone/ Control 25 ± 8  tetrahydrofuran/H₂O Resveratrol20% = 0.2 mg/mg N 21 ± 6  paclitaxel; acetone/ tetrahydrofuran/H₂OResveratrol 50% = 0.5 mg/ O  7 ± 11 mg paclitaxel; acetone/tetrahydrofuran/H₂O

EXAMPLE 4

Balloons for percutaneous transluminal coronary angioplasty type A werecoated in already folded condition either with paclitaxel without orwith polyacrylic acid. Polyacrylic olyacrylic acid (molecular weightabout 6000 D (Polysciences Inc., USA) and glycerol improved thehomogeneity of the coating on the balloon.

Coating solution Labeling Distribution on balloons Paclitaxel without NSpreading limited to polyacrylic acid acetone/ directly accessiblesurface tetrahydrofuran/H₂O 0.8 mg polyacrylic acid + D Irregulardistribution, 0.06 mg glycerol/mg partly below the folds paclitaxelacetone/ tetrahydrofuran/H₂O 0.15 mg polyacrylic acid + E Almosthomogeneous 0.06 mg glycerol/mg distribution including paclitaxel inacetone/ areas below the folds tetrahydrofuran/H₂O

1-12. (canceled)
 13. A balloon catheter for angioplasty or coronaryangioplasty comprising: a shaft having a proximal portion and a distalportion; an inflatable balloon coupled to the distal portion of theshaft; a nonimplantable scoring structure surrounding the balloon,wherein the scoring structure is capable of scoring a luminal surface ofa blood vessel upon inflation of the inflatable balloon; wherein theballoon catheter carries on at least on a portion of its surface atherapeutically effective amount of at least one oxidation-insensitivedrug and an amount of at least one lipophilic antioxidant that is 3-100%by weight of the drug, wherein the at least one oxidation-insensitivedrug is selected from the group consisting of: taxanes, thalidomide,statins, corticoids and lipophilic derivatives of corticoids, and the atleast one lipophilic antioxidant is selected from the group consistingof: nordihydroguaiaretic acid, resveratrol and propyl gallate.
 14. Theballoon catheter according to claim 13, wherein the scoring structurecomprises one or more wires capable of scoring the luminal surface uponinflation of the inflatable balloon.
 15. The balloon catheter accordingto claim 13, wherein the oxidation-insensitive drug is a taxane selectedfrom the group consisting of paclitaxel, protaxel and docetaxel.
 16. Theballoon catheter according to claim 15, wherein the at least onelipophilic antioxidant is nordihydroguaiaretic acid.
 17. The ballooncatheter according to claim 15, wherein the taxane is paclitaxel. 18.The balloon catheter according to claim 17, wherein the at least onelipophilic antioxidant is nordihydroguaiaretic acid.
 19. The ballooncatheter according to claim 13, wherein the at least one lipophilicantioxidant is nordihydroguaiaretic acid.
 20. The balloon catheteraccording to claim 13, wherein the amount of the at least one lipophilicantioxidant protects the drug from premature loss during delivery to anangioplasty site.
 21. The balloon catheter according to claim 13,wherein the at least one antioxidant load is up to 10 μg/mm2 of coatedcatheter surface.
 22. The balloon catheter according to claim 21,wherein the at least one lipophilic antioxidant is nordihydroguaiareticacid.
 23. The balloon catheter according to claim 13, wherein the atleast one lipophilic antioxidant is contained at a ratio of 5-100% byweight, in relation to 100% by weight of the at least oneoxidation-insensitive drug.
 24. The balloon catheter according to claim23, wherein the at least one lipophilic antioxidant isnordihydroguaiaretic acid and the at least one oxidation-insensitivedrug is paclitaxel.
 25. The balloon catheter according to claim 13,wherein the at least one lipophilic antioxidant is contained at a ratioof 10-100% by weight, in relation to 100% by weight of the at least oneoxidation-insensitive drug.
 26. The balloon catheter according to claim25, wherein the at least one lipophilic antioxidant isnordihydroguaiaretic acid and the at least one oxidation-insensitivedrug is paclitaxel.
 27. The balloon catheter according to claim 13,wherein the at least one lipophilic antioxidant is contained at a ratioof 20-100% by weight, in relation to 100% by weight of the at least oneoxidation-insensitive drug.
 28. The balloon catheter according to claim27, wherein the at least one lipophilic antioxidant isnordihydroguaiaretic acid and the at least one oxidation-insensitivedrug is paclitaxel.
 29. The balloon catheter according to claim 13,wherein the at least one lipophilic antioxidant is contained at a ratioof 50-100% by weight, in relation to 100% by weight of the at least oneoxidation-insensitive drug.
 30. The balloon catheter according to claim29, wherein the at least one lipophilic antioxidant isnordihydroguaiaretic acid and the at least one oxidation-insensitivedrug is paclitaxel.
 31. The balloon catheter according to claim 13,further comprising a coating composition including the therapeuticallyeffective amount of at least one oxidation-insensitive drug and anamount of at least one lipophilic antioxidant, wherein the coatingcomposition is polymer-free.
 32. The balloon catheter according to claim31, wherein the at least one lipophilic antioxidant isnordihydroguaiaretic acid and the at least one oxidation-insensitivedrug is paclitaxel.